11-3013840-T-C

Variant names:

• chr11-3013840-T-C
• rs12421922
• NM_001014437.3:c.1987-1564A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001014437.3(CARS1):​c.1987-1564A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 151,652 control chromosomes in the GnomAD database, including 9,620 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.32 (9620 hom., cov: 31)
• Consequence: CARS1 NM_001014437.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.207
• Publications: 10 publications found

Genes affected

CARS1 (HGNC:1493): (cysteinyl-tRNA synthetase 1) This gene encodes a class 1 aminoacyl-tRNA synthetase, cysteinyl-tRNA synthetase. Each of the twenty aminoacyl-tRNA synthetases catalyzes the aminoacylation of a specific tRNA or tRNA isoaccepting family with the cognate amino acid. This gene is one of several located near the imprinted gene domain on chromosome 11p15.5, an important tumor-suppressor gene region. Alterations in this region have been associated with Beckwith-Wiedemann syndrome, Wilms tumor, rhabdomyosarcoma, adrenocortical carcinoma, and lung, ovarian and breast cancers. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Aug 2010]

CARS1 Gene-Disease associations (from GenCC):

• microcephaly, developmental delay, and brittle hair syndrome

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.615 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001014437.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARS1	NM_001014437.3	MANE Select	c.1987-1564A>G		intron	N/A	NP_001014437.1	P49589-3
	CARS1	NM_001194997.2		c.1987-1564A>G		intron	N/A	NP_001181926.1
	CARS1	NM_001751.6		c.1738-1564A>G		intron	N/A	NP_001742.1	P49589-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARS1	ENST00000380525.9	TSL:1 MANE Select	c.1987-1564A>G		intron	N/A	ENSP00000369897.4	P49589-3
	CARS1	ENST00000397111.9	TSL:1	c.1738-1564A>G		intron	N/A	ENSP00000380300.5	P49589-1
	CARS1	ENST00000278224.13	TSL:1	c.1738-1564A>G		intron	N/A	ENSP00000278224.9	P49589-2

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48454 AN: 151536 Hom.: 9610 Cov.: 31

Gnomad AFR AF: 0.0907

Gnomad AMI AF: 0.534

Gnomad AMR AF: 0.482

Gnomad ASJ AF: 0.412

Gnomad EAS AF: 0.632

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.310

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.384

Gnomad OTH AF: 0.346

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.320 AC: 48478 AN: 151652 Hom.: 9620 Cov.: 31 AF XY: 0.322 AC XY: 23859 AN XY: 74124

African (AFR) AF: 0.0906 AC: 3743 AN: 41308

American (AMR) AF: 0.483 AC: 7372 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.412 AC: 1427 AN: 3462

East Asian (EAS) AF: 0.633 AC: 3245 AN: 5128

South Asian (SAS) AF: 0.426 AC: 2050 AN: 4816

European-Finnish (FIN) AF: 0.310 AC: 3259 AN: 10504

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.384 AC: 26052 AN: 67864

Other (OTH) AF: 0.350 AC: 738 AN: 2106

Alfa AF: 0.370 Hom.: 6169

Bravo AF: 0.321

Asia WGS AF: 0.503 AC: 1747 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.0
DANN	Benign	0.28
PhyloP100		0.21
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12421922; hg19: chr11-3035070;